Animal models play a fundamental role in the strategy currently envisioned for vaccine development against bioterrorism agents. Vaccine development may have to rely on human Phase I safety and vaccine efficacy data in animal models (likely to be represented by non-human primates) as Phase II efficacy trials may not be possible, lacking (hopefully) exposed and at-risk individuals. Accurate and quantitative assessment of immune responses is essential for the development of animal models, which are crucial to devising vaccination strategies as well as enhancing our understanding of disease pathogenesis. To systematically define immunodominant antigens and epitopes in the various animal species utilized (and in humans as well) is, however, a daunting task, especially when the impact of MHC polymorphism is taken into account. In the present application, we propose exploring an alternative approach. Specifically, we will define sets of macaque (Mamu) MHC molecules associated with epitope specificities that are highly overlapping with the most frequently occurring human HLA molecules. The relevance of the cross-reaction observed at the level of MHC binding and primary immunogenicity will be tested by evaluating the recognition of specific epitopes following influenza infection in MHC-typed macaques and the general human population. Definition of matching sets of analogous MHC molecules in non-human primates and humans would allow, by judicious use of MHC-typed macaques, to study immune responses in macaques utilizing the same epitopes recognized by humans. This will enhance the relevance of macaque models of human immune responses. Additionally, this will provide the means for testing epitope-based vaccines and diagnostic reagents destined for human use in non-human primate models of infection and vaccination. To maximize coverage of the general human population and of the populations of rhesus macaques utilized in animal model studies, molecules commonly expressed in high frequencies have been selected for study. In conclusion, the proposed studies will provide a unique opportunity to use macaque animal models for the study of immune responses restricted by HLA antigens expressed with high frequency in humans.